This is a submission for partial support of a pivotal Phase 3 study responsive to PAR-18-028. The clinical trial uses a novel approach to Alzheimer?s disease in patients at high risk for dementia. It will test the efficacy of a low-dose formulation of the SV2a antagonist levetiracetam (AGB101) to slow disease progression in patients with amnestic Mild Cognitive Impairment (aMCI) due to Alzheimer?s disease (AD). The entire Phase 3 program will include 830 patients randomly assigned to either AGB101 or placebo and followed for 78 weeks using the Clinical Dementia Rating sum of boxes (CDRsb) as a sole primary efficacy measure as agreed upon with the FDA at the End of Phase 2 meeting. As partial support for the trial under a public private partnership, the funds requested in this application support a substudy of 160 patients (out of the total 830), who will follow the full phase 3 protocol with the addition of tau PET imaging at baseline and endpoint to assess the effect of AGB101 on the spread of tau pathology. Extensive clinical and preclinical data support the hypothesis that neural overactivity is a critical driver of neuropathology leading to neuronal death in early AD and strongly support the hypothesis that hippocampal overactivity is a driver of the spread of tau pathology. This overactivity is most prominent in patients with clinical MCI and deposited amyloid as determined by amyloid PET imaging (aMCI due to AD). As described in the application, extensive preclinical data also show that the antiepileptic drug levetiracetam given in low, but not at the much higher doses used to treat epilepsy, restores hippocampal activity to normal levels and prevents neurodegeneration; other antiepileptic drugs that are not SV2a antagonists do not have this neurobiological effect. A Phase 2 study measuring hippocampal activity during a pattern separation memory test in patients with aMCI found that AGB101 normalized hippocampal activity and improved performance on this highly specific memory test for assessment of hippocampal function. Most importantly, the proposed substudy will provide a robust test of the ability of AGB101 to restore normal hippocampal activity when given chronically and the relationship of this normalization to the spread of tau pathology as assessed in tau PET imaging together with a longitudinal series of 3T MRI structural imaging optimized for the medial temporal lobe circuits the define early Braak staging. Thus, alongside partial support for the Phase 3 trial, with possible registration of a new therapeutic by 2021, support under this award will potentially contribute to biomarker development by testing the hypothesis that excess neural activity drives disease progression, specifically the spread of tau pathology.